Adaptation of pancreatic islets to insulin resistance plays critical role in the maintenance of normoglycemia in obesity (1). However, in some patients islet adaptation is attenuated, leading to the onset of diabetes (2). Currently the underlying mechanisms for islet adaptation to obesity are not well understood. Interestingly Neuropeptide Y (NPY), a peptide in the brain that is known to play an important role in the development of obesity, is also found in the pancreatic islets and may integrate energy homeostasis and glucose homeostasis (3). The expression of pancreatic NPY and its receptor is markedly decreased in obese, insulin resistant, hyperinsulinemic mice (3). Moreover NPY deficient islets are larger and have higher insulin secretion implying that NPY acts through a paracrine or autocrine mechanism to tonically inhibit insulin secretion (3). Therefore it is hypothesized that the suppression of pancreatic NPY seen in obesity serves as one of the mechanisms to increase insulin secretion and prevents the development of diabetes in insulin resistant status. To test the hypothesis the mouse model that maintains the expression of NPY transgenically in islets and is prevented from the down-regulation of NPY during the development of obesity will be established. The expression level of NPY transgene is aimed at the level comparable to the physiological level seen in non-obese mouse. Then the mouse will be placed on high fat diet to address whether the prevention of down-regulation of NPY in the pancreatic islets interferes with the enhancement of insulin secretion and accelerates the development of diabetes in diet-induced obesity. Secondly the tonic effects of NPY on insulin secretion and its survival will be clarified. Pancreatic islets from Npy null mice will be infected with adenovirus containing NPY cDNA to achieve chronic exposure to NPY in culture. Thereafter glucose-stimulated insulin secretion and apoptosis will be compared between islets transduced with NPY adenovirus and control. The study is the expansion of the on going project by the principal investigator supported by a K08 grant that addresses both central and pancreatic role of NPY in the regulation of insulin secretion using NPY deficient mice. These study aim to address the role of NPY in glucose homeostasis and have potential to reveal a new mechanism that prevents the development of diabetes in obesity. In addition to deepening our knowledge of islet adaptation in obesity, the project will provide crucial funding for the principal investigator, Dr. Imai, to increase her independency in research and to establish her academic career in Diabetes/Endocrinology. The NPY transgene model has a great potential to develop into a new project for future R01 application. The study will be carried out in the Institute of Diabetes, Obesity and Metabolism and the Division of Endocrinology, Diabetes, and Metabolism at the University of Pennsylvania under the supervision of Dr. Rexford Ahima and Dr. Franz Matschinsky. The institute has expertise in diabetes and obesity research, and will provide outstanding environment to conduct the proposed project. PUBLIC HEALTH RELEVANCE: The project will address the role of neuropeptide Y in pancreatic islets in the regulation of insulin secretion and glucose homeostasis. The study has a potential to reveal a new mechanism to increase insulin secretion in obesity and prevent the development of diabetes in obesity.